Altered serotonin (5-HT) biogenic amine functions within the central nervous system (CNS) are involved or have been implicated in a number of mental health disorders and clinical therapies. The determination of pre-synaptic serotonin transporter (SERT) populations in discrete cerebral regions of living brain may serve as an indicator of the 5-HT system in health and disease. Regional cerebral SERT density measurements with positron emission tomography (PET) imaging are valuable assessments of 5-HT terminal integrity in living brain. Since SERT densities vary as a function of cerebral region, (e.g., high-midbrain, hypothalamus; modest-limbic system, hippocampus and frontal cortex; and low-cerebellum reference region) and with disease (e.g., within the limbic system and neocortical region, among other regions), clinical PET imaging studies demand reproducible measurements of a range of SERT densities (low to high) across live brain regions. Potent SERT tracers (positron labeled radioligands) with appropriate in vivo profiles (brain penetration, target-to-reference tissue ratios, target tissue specific binding to particular protein, among others) are required. These in vivo tracer performance parameters as a function of evaluating CNS 5-HT integrity with cerebral PET imaging for have recently been discussed [Hesse 2004].
Primate brain SERT PET tracer investigations [Elfving 2001, Frankle 2004, Huang 2004, Huang 2002] have brought forward a refined SERT tracer hypothesis, which contends that candidate imaging tracers suitable for assessing low-high SERT densities are plausible, prospectively when the tracers possess the certain traits, for example: i) high SERT binding affinity, ii) reduced nonspecific (reference region; e.g., cerebellum) binding, and iii) extended kinetic imaging profiles as a function of the enhanced radioligand affinity, compensated for with longer-lived radionuclides (e.g., fluorine-18) that provide extended timeframes for PET scan data collections affording accurate estimates of in vivo SERT densities. A need remains for new and effective image tracers. The identification of tracers possessing the aforementioned in vitro and in vivo qualities solves this problem.
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